There is strong evidence that defective mitochondria and impaired energy substrate metabolism contributes to the contractile dysfunction and poor mechanical efficiency of the left ventricle in heart failure. The overall theme of this Program Project Grant is the identification of abnormalities of myocardial energy metabolism that occur with heart failure, and the effects of these abnormalities on left ventricular function and remodeling. This Project fits into that theme by assessing the biochemical defects in myocardial energy substrate metabolism during the course of evolving heart failure and the consequences of these defects on left ventricular contractile function under resting conditions and when cardiac function is stressed by adrenergic stimulation. The goal of this project is to understand how defects in myocardial energy metabolism affect the mechanical function and efficiency of the left ventricle in heart failure. Several lines of evidence suggest that the contractile performance of the heart is greater for a given rate of myocardial oxygen consumption when the heart is oxidizing carbohydrate rather than fatty acids. We hypothesize that acutely switching substrate oxidation from fatty acid to carbohydrate oxidation in mild to moderate severity heart failure will improve cardiac function, particularly during stress. The canine multiple sequential intracoronary microembolization model will be used to reduce ejection fraction to 30%, and heart failure will be allowed to progress for up to 16 weeks (left ventricular ejection fraction equal to or < 20%). Terminal studies to assess metabolic and contractile dysfunction will be made at 0, 6, 12 or 16 weeks. The Specific Aims of the project are 1) elucidate the changes in substrate metabolism and metabolic regulation over the course of heart failure. 2) acutely manipulate fatty acid and pyruvate oxidation under normal and stressed conditions to identify key sites of metabolic dysfunction and the effect of contractile function, and 3) understand the role of malonyl-CoA inhibition in the inter-regulation of fatty acid and pyruvate oxidation in heart failure.